WO1998051681A1 - New intermediates and process for the preparation thereof - Google Patents

New intermediates and process for the preparation thereof Download PDF

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Publication number
WO1998051681A1
WO1998051681A1 PCT/HU1998/000047 HU9800047W WO9851681A1 WO 1998051681 A1 WO1998051681 A1 WO 1998051681A1 HU 9800047 W HU9800047 W HU 9800047W WO 9851681 A1 WO9851681 A1 WO 9851681A1
Authority
WO
WIPO (PCT)
Prior art keywords
chlorophenyl
general formula
thienyl
ethylamino
salts
Prior art date
Application number
PCT/HU1998/000047
Other languages
English (en)
French (fr)
Inventor
Mária Bakonyi
Marianna CSATÁRINÉ NAGY
Leventéné MOLNÁR
Zoltán MAKOVI
Piroska Jobb
Tiborné BAI
Original Assignee
Sanofi-Synthelabo
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sanofi-Synthelabo filed Critical Sanofi-Synthelabo
Priority to US09/423,801 priority Critical patent/US6258961B1/en
Priority to DE69813792T priority patent/DE69813792T2/de
Priority to JP54895598A priority patent/JP4282770B2/ja
Priority to CA002289545A priority patent/CA2289545C/en
Priority to DK98921669T priority patent/DK0981524T3/da
Priority to EP98921669A priority patent/EP0981524B1/en
Priority to AT98921669T priority patent/ATE238294T1/de
Priority to BRPI9809111-5A priority patent/BR9809111B1/pt
Priority to AU74447/98A priority patent/AU7444798A/en
Publication of WO1998051681A1 publication Critical patent/WO1998051681A1/en
Priority to NO19995532A priority patent/NO324039B1/no

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms

Definitions

  • This invention relates to the new intermediates of general formula (VII) - wherein X stands for halogen atom - and to the process of their preparation. It is known that methyl (2-halogenophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyridin- 5-yl)acetates and their salts can favourably be used in the treatment, first of all owing to their platelet-aggregation-inhibitory and antithrombotic effects.
  • each intermediate is chiral, in the preparation of an optically active end-product, as for instance clopidogrel, the possibility is open to use - from the first step on- optically active compounds as intermediates.
  • the economical benefit of the method is among others the avoidance of preparation of an unwanted isomer.
  • optically active compounds of general formula (VII) are prepared either from the optically active compounds of general formula (I) by the process according to our invention, or by resolving the racemic compound of general formula (VII) to its optical isomers.
  • a racemic or optically active compound of general formula (I) - wherein the meaning of X is as defined above - or its salts are transformed, and if desired, the resulting racemic compound of general formula (VII) is resolved to its optically active isomers, and if desired the racemic compound or the optically active isomers are transformed into their salts, or the racemic compound or the optically active isomers are liberated from their salts.
  • the reaction of the compounds of general formula (I) with methanol and hydrochloric acid is performed in dry organic solvent.
  • organic solvent alkyl acetates such as for instance methyl acetate or ethyl acetate may favourably be applied.
  • the reaction is carried out at a temperature between 0 °C and +60 °C, preferably between 10 °C and 50 °C.
  • the optically active compounds of general formula (VII) are prepared either from the optically active compounds of general formula (I) by the route according to our invention, or by resolution of the racemic compound of general formula (VII).
  • numerous chiral acids may be applied, very advantageous is the application of L-(+)-tartaric acid in the presence of formic acid and isopropanol.
  • the crystalline aldehyde bisulfite transforms into an oily material.
  • the mixture is cooled to room temperature and the solution of 49 g (1 mol) of sodium cyanide in 100 ml of water is added to it. During the addition the temperature of the reaction mixture raises to 40°C. The mixture is then stirred at 60 °C till the reaction is completed ( 1 hour).
  • the oily organic phase is then extracted with 400 ml of 1,2-dichloroethane, washed to cyanide-free with 2x200 ml of water, traces of 2-(2-thienyl)ethylamine are removed by treatment with 100 ml of 3% hydrochloric acid solution.
  • the dichloroethane phase was dried over anhydrous sodium sulfate and evaporated in vacuo.
  • the residual fast crystallizing oil is the product. Weight: 260 g (94 %) mp. : 40-41 °C.
  • the product was identified by elementary analysis, IR spectrum and 1H-NMR investigation.
  • 9,8 g (0,2 mol) of sodium cyanide is dissolved in 70 ml of water and to the solution first 32,8 g (0,2 mol) of 2-(2-thienyl)ethylamine hydrochloride, then in a period of a few minutes, the solution of 28,2 g (0,2 mol) of o-chlorobenzaldehyde in 30 ml of ethanol are added. During the addition the temperature of the mixture raises to 45 °C. The reaction mixture is then stirred at 60 °C for 2 hours, then cooled to room temperature and diluted with 50 ml of water.
  • the resulting oily product is extracted with 100 ml of 1,2-dichloroethane, the organic phase is washed to cyanide-free with 2x50 ml of water, the traces of 2-(2-thienyl)ethylamine are removed by treatment with 20 ml of 3% hydrochloric acid solution.
  • the residual fast crystallizing oil is the product.
  • the product was identified as written in Example 1. Quality of the product is identical with that of the product prepared according to Example 1.
  • the product was identified by elementary analysis, IR spectrum and ' H-NMR investigation.
  • the aqueous layer is extracted with 2x30 ml of 1,2-dichloroethane, the combined organic layers are washed with 80 ml of 5% sodium hydroxide solution, then with 100 ml of water, dried over anhydrous sodium sulfate and evaporated in vacuo. Weight of the residue: 28,5 g.
  • the oily product which is the base of formula (VIII), is dissolved in 50 ml of isopropyl acetate, 7,3 ml (0,087 mol) of concentrated hydrochloric acid solution is added to it, and the mixture is stirred at room temperature for 1 hour. The precipitating product is filtered off, washed with 2x10 ml of isopropyl acetate and dried. Weight: 28,4 g (82 %) mp.: 177-178 °C (lit. 175 °C). The product was identified by elementary analysis, IR spectrum, 1H-NMR.and MS investigation and mp. determination.
  • Methyl[2-(2-thienyl)ethylamino](2-chlorophenyl)acetate hydrochloride In 150 ml of methanol 8,5 ml (0, 15 mol) of 96 % sulfuric acid is dissolved under cooling and the solution is then heated under reflux conditions for 1/2 hour. After cooling to room temperature 20 g (0,0678 mol) of [2-(2-thienyl)ethylamino](2- chlorophenyl)acetamide, falling under general formula (VII) and prepared as described in Example 7., is added to the solution, the mixture is placed into a closed apparatus (autoclave) and stirred in it at 130 °C-on for 5 hours, while the inner pressure elevates to 13 bar.
  • autoclave autoclave
  • reaction mixture is then cooled to room temperature (remaining pressure 1-2 bar), the methanol is distilled off in vacuo and to the residue 100 ml of isopropyl acetate and 100 ml of water are added and the pH of the mixture is adjusted to 7,5 by dropwise addition of 60 ml of 10 % sodium hydroxide solution, under cooling and stirring, while keeping the mixture at room temperature.
  • the phases are separated, the organic phase is stirred with 60 ml of 3% aqueous maleic acid solution at 40-50 °C for 10 minutes, the two phases are then separated.
  • the residual 25 g material (acetate base) is dissolved in 90 ml of formic acid, to the solution 4 g (0, 13 mol) of paraformaldehyde is added and the mixture is stirred at 50 °C for 20 minutes.
  • the majority of the formic acid is then distilled off in vacuo, the residue is dissolved in the mixture of 100 ml of water and 100 ml of 1,2-dichloroethane, the phases are separated, the aqueous phase is extracted again with 30 ml of 1,2-dichloroethane, the combined organic phase is shaken well with 100 ml of 5% sodium hydrogen carbonate solution, the phases are separated and the organic phase is dried over anhydrous sodium sulfate and evaporated in vacuo.
  • the product was identified by elementary analysis, IR spectrum and ' H-NMR investigation.
  • the product was identified by elementary analysis, IR spectrum and ' H-NMR investigation.
  • Dextrorotatory [2-(2-thienyl)ethylamino](2-chlorophenyl)acetamide 38 g (0, 129 mol) of racemic [2-(2-thienyl)ethylamino](2-chlorophenyl)acetamide is dissolved at 50 °C in 380 ml of isopropanol containing 0-0,4% advantageously 0,2%) of water and to this solution is added the 50 °C solution of 10,6 g (0,071 mol) of L(+)-tartaric acid in 230 ml of isopropanol, containing 0-0,4%, advantageously 0,2% of water. The mixture is stirred at 50 °C for 30 minutes.
  • Thick, white precipitate is formed.
  • 34 ml (0,09 mol) of formic acid is added and stirring is continued at 50 °C for 1 hour.
  • the reaction mixture is then cooled to room temperature, stirred for another hour and the solid phase is filtered off
  • the precipitated material is the salt formed between the laevorotatory enantiomer of the starting material and L(+)-tartaric acid, in an optically slightly contaminated form.
  • Weight 30 g. Mp.: 167 - 169 °C, after crystallization from ethanol. The mother liquor is evaporated in vacuo.
  • the residue ( 29 g) is taken up in 200 ml of water and 200 ml of 1,2-dichloroethane and neutralized under stirring with 16 g (0, 19 mol) of sodium hydrogen carbonate.
  • the phases are separated, the aqueous layer is washed with 2x30 ml of 1,2-dichloroethane, the combined organic layer is extracted with 50 ml of water, dried over anhydrous sodim sulfate and evaporated in vacuo.
  • the raw product is recrystallized from 70 ml of ethanol, washed with a small amount of ethanol and dried. Weight: 12,6 g.
  • the precipitated material is the salt formed between the laevorotatory enantiomer of the starting material and L(+)-tartaric acid is an optically slightly contaminated form.
  • Dextrorotatory methyl[2-(2-thienyl)ethylamino](2-chlorophenyl)acetate- hydrochloride In 40 ml of methanol under cooling 11,5 ml (0,215 mol) of 100% sulfuric acid is dissolved, the solution is heated under reflux conditions for 30 minutes, then after cooling to room temperature 12,4 g (0,042 mol) of dextrorotatory [2-(2- thienyl)ehylamino](2-chlorophenyl)acetamide is added and the mixture is heated under reflux for 6-7 hours, till the end of the reaction.
  • Methanol is distilled off in vacuo, to the residue 75 ml of 1,2-dichloroethane and 75 ml of water are added, the mixture is shaken well and the phases are separated.
  • the aqueous phase is extracted with 2x20 ml of 1,2-dichloroethane, the united organic phase is extracted with 50 ml of 5% sodium hydroxide solution then with 50 ml of water, dried over anhydrous sodium sulfate.
  • the drying material is filtered off and 1,5 g (0,041 mol) of dry hydrogen chloride gas is introduced under cooling into the solution.
  • the precipitated crystalline product is filtered off, washed with 1,2- dichloroethane and dried.
  • Example 21 Example 21.
  • the aqueous phase is extracted with 2x30 ml of 1,2- dichloroethane, the united organic phase is extracted with 100 ml of water, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo.
  • the residual 6 g of material is dissolved in 30 ml of diethyl ether, and while cooling the reaction mixture, 0,6 g of dry hydrogen chloride gas is introduced into the solution, at room temperature.
  • the precipitated crystalline material is filtered off, washed with ether and dried.
  • Weight: 5,5 g. Mp.: 130 - 132 °C, [ ⁇ ] 22 D + 60 °. Yield: 90, 1%.
  • Example 22 a) (+)-(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetic acid methyl ester (-)-camphorsulfonic acid salt
  • (+)-(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetic acid methyl ester To the suspension made of 200 g of (+)-(2-chlorophenyl)(6,7-dihydro-4H- thieno[3,2-c]pyridin-5-yl)acetic acid methyl ester (-)-camphorsulfonic acid salt and 800 ml of dichloromethane is added 800 ml of sodium hydrogene carbonate solution. After stirring the organic phase is separated by decantation, dried on sodium sulfate and the solvent is removed in vacuo.
  • (+)-(2-chlorophenyl)(6,7- dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetic acid methyl ester is obtained as a solution in 800 ml of dichloromethane. After stirring, the organic phase is separated by decantation, dried over sodium sulfate and the solvent is removed in vacuo.
  • the (+)-(2-chlorophenyl)(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetic acid methyl ester is obtained in the form of colourless oil.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Press Drives And Press Lines (AREA)
  • Steroid Compounds (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
PCT/HU1998/000047 1997-05-13 1998-05-11 New intermediates and process for the preparation thereof WO1998051681A1 (en)

Priority Applications (10)

Application Number Priority Date Filing Date Title
US09/423,801 US6258961B1 (en) 1997-05-13 1998-05-11 Intermediates and process for the preparation thereof
DE69813792T DE69813792T2 (de) 1997-05-13 1998-05-11 Zwischenprodukte und verfahren zu ihrer herstellung
JP54895598A JP4282770B2 (ja) 1997-05-13 1998-05-11 新規な中間体およびその製造方法
CA002289545A CA2289545C (en) 1997-05-13 1998-05-11 Process for the preparation of 2-[(2-thienyl)-ethylamino]-(2-halogenophenyl)acetamides
DK98921669T DK0981524T3 (da) 1997-05-13 1998-05-11 Nye mellemprodukter og fremgangsmåde til fremstilling deraf
EP98921669A EP0981524B1 (en) 1997-05-13 1998-05-11 New intermediates and process for the preparation thereof
AT98921669T ATE238294T1 (de) 1997-05-13 1998-05-11 Zwischenprodukte und verfahren zu ihrer herstellung
BRPI9809111-5A BR9809111B1 (pt) 1997-05-13 1998-05-11 intermediários de [2-(2-tienil) etilamino]-(2-clorofenil) acetamida e processo para preparação dos mesmos.
AU74447/98A AU7444798A (en) 1997-05-13 1998-05-11 New intermediates and process for the preparation thereof
NO19995532A NO324039B1 (no) 1997-05-13 1999-11-12 Nye mellomprodukter og fremgangsmate for fremstilling derav

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HU9700884A HU225503B1 (en) 1997-05-13 1997-05-13 Novel 2-(2-halophenyl)-2-(2-(2-thienyl)-ethylamino)-acetamides and process for producing them
HUP9700884 1997-05-13

Publications (1)

Publication Number Publication Date
WO1998051681A1 true WO1998051681A1 (en) 1998-11-19

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US (1) US6258961B1 (hu)
EP (1) EP0981524B1 (hu)
JP (1) JP4282770B2 (hu)
AT (1) ATE238294T1 (hu)
AU (1) AU7444798A (hu)
BR (1) BR9809111B1 (hu)
CA (1) CA2289545C (hu)
DE (1) DE69813792T2 (hu)
ES (1) ES2195335T3 (hu)
HU (1) HU225503B1 (hu)
NO (1) NO324039B1 (hu)
PT (1) PT981524E (hu)
WO (1) WO1998051681A1 (hu)

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000027840A1 (en) * 1998-11-09 2000-05-18 Sanofi-Synthelabo Process for racemization
US6495691B1 (en) 2001-07-06 2002-12-17 Brantford Chemicals Inc. Process for the preparation of tetrahydrothieno[3,2-c]pyridine derivatives
WO2003035652A1 (en) * 2001-10-26 2003-05-01 Merck Generics [Uk] Limited A PROCESS FOR PREPARING ENANTIOMERICALLY PURE α-PHENYL-α-(6,7-DIHYDRO-4H-THIENO[3,2-C]PYRIDIN-5-YL)-ACETIC ACID DERIVATIVES
US6737411B2 (en) * 2002-08-02 2004-05-18 Teva Pharmaceutical Industries Ltd. Racemization and enantiomer separation of clopidogrel
US6767913B2 (en) 2001-12-18 2004-07-27 Teva Pharmaceutical Industries Ltd. Crystal forms iii, iv, v, and novel amorphous form of clopidogrel hydrogensulfate, processes for their preparation, processes for the preparation of form i, compositions containing the new forms and methods of administering the new forms
WO2004081016A1 (en) 2003-03-12 2004-09-23 Cadila Healthcare Limited Polymorphs and amorphous form of (s) - (+) -clopidogrel bisulfate
US6800759B2 (en) * 2002-08-02 2004-10-05 Teva Pharmaceutical Industries Ltd. Racemization and enantiomer separation of clopidogrel
WO2004094374A2 (en) * 2003-04-23 2004-11-04 Rhodia Pharma Solutions Inc. (Formally Rhodia Chirex Inc.) Preparation of (s)-clopidogrel and related compounds
WO2004108665A2 (en) * 2003-04-24 2004-12-16 Sun Pharmaceutical Industries Limited A process for preparation of clopidogrel
US7074928B2 (en) 2002-01-11 2006-07-11 Teva Pharmaceutical Industries, Ltd. Polymorphs of clopidogrel hydrogensulfate
WO2008118030A1 (en) * 2007-03-23 2008-10-02 Tomasz Kozluk Process for preparation of pure polymorphic form 1 of clopidogrel hydrogensulfate
EP1980563A1 (en) 2007-04-09 2008-10-15 BATTULA, Srinivasa Reddy Procedure for the preparation of methyl (+)-(S)-Alpha-(O-chlorophenyl)-6,7-dihydrothieno-[3,2-C]pyridine-5(4H) acetate
EP2103617A1 (en) 2003-11-03 2009-09-23 Cadila Healthcare Limited Processes for preparing different forms of (S)-(+)-clopidogrel bisulfate
EP2149578A1 (en) 2003-09-11 2010-02-03 Merck Generics (UK) Limited Novel crystalline polymorphs of clopidogrel
CN103483356A (zh) * 2013-09-30 2014-01-01 浙江美诺华药物化学有限公司 一种（s）-氯吡格雷的硫酸盐或盐酸盐的制备方法

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* Cited by examiner, † Cited by third party
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PL1589019T3 (pl) * 2004-04-20 2008-12-31 Ratiopharm Gmbh Stereoselektywny sposób wytwarzania klopidogrelu
WO2006034451A2 (en) * 2004-09-21 2006-03-30 Teva Pharmaceutical Industries Ltd. Crystalline clopidogrel hydrobromide and processes for preparation thereof
MX2007010267A (es) * 2005-02-24 2007-09-11 Teva Pharma Base de clopidogrel adecuada para formulacion farmaceutica y preparacion de ella.
CA2650471A1 (en) * 2006-04-27 2007-11-08 Ind-Swift Laboratories Limited Process for the preparation of polymorphic forms of clopidogrel hydrogen sulfate
CA2655844A1 (en) * 2006-08-03 2008-02-14 Teva Pharmaceutical Industries Ltd. Process for preparing clopidogrel bisulphate
EP2107061A1 (en) 2008-04-02 2009-10-07 Krka Tovarna Zdravil, D.D., Novo Mesto Process for the preparation of optically enriched clopidogrel
US20090264460A1 (en) * 2008-04-21 2009-10-22 Mamta Mishra Clopidogrel pharmaceutical formulations
EP2346879A1 (en) * 2008-10-24 2011-07-27 Sandoz AG A process for the preparation of s-clopidogrel
US8563690B2 (en) * 2008-11-03 2013-10-22 The Board Of Trustees Of The University Of Illinois Modulation of platelet aggregation

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0099802A1 (fr) * 1982-07-13 1984-02-01 Elf Sanofi Nouveaux dérivés de la thiéno-(3,2-c) pyridine, leur procédé de préparation et leur application thérapeutique
US4847265A (en) * 1987-02-17 1989-07-11 Sanofi Dextro-rotatory enantiomer of methyl alpha-5 (4,5,6,7-tetrahydro (3,2-c) thieno pyridyl) (2-chlorophenyl)-acetate and the pharmaceutical compositions containing it
EP0420706A2 (fr) * 1989-09-29 1991-04-03 Sanofi Procédé de préparation de dérivés phénylacétiques de thiÀ©nopyridines et des acides alpha-bromo phénylacétiques intermédiaires
EP0466569A1 (fr) * 1990-07-10 1992-01-15 Sanofi Procédé de préparation d'un dérivé N-phénylacétique de tétrahydro-thiéno (3,2-c) pyridine et son intermédiaire de syntèse

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2608607B1 (fr) 1986-12-23 1989-04-28 Sanofi Sa Procede de preparation de thienylethylamines et dithienylethylamines ainsi obtenues

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0099802A1 (fr) * 1982-07-13 1984-02-01 Elf Sanofi Nouveaux dérivés de la thiéno-(3,2-c) pyridine, leur procédé de préparation et leur application thérapeutique
US4847265A (en) * 1987-02-17 1989-07-11 Sanofi Dextro-rotatory enantiomer of methyl alpha-5 (4,5,6,7-tetrahydro (3,2-c) thieno pyridyl) (2-chlorophenyl)-acetate and the pharmaceutical compositions containing it
EP0420706A2 (fr) * 1989-09-29 1991-04-03 Sanofi Procédé de préparation de dérivés phénylacétiques de thiÀ©nopyridines et des acides alpha-bromo phénylacétiques intermédiaires
EP0466569A1 (fr) * 1990-07-10 1992-01-15 Sanofi Procédé de préparation d'un dérivé N-phénylacétique de tétrahydro-thiéno (3,2-c) pyridine et son intermédiaire de syntèse

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000027840A1 (en) * 1998-11-09 2000-05-18 Sanofi-Synthelabo Process for racemization
US6670486B1 (en) 1998-11-09 2003-12-30 Sanofi-Synthelabo Process for racemization
US7109356B2 (en) 1998-11-09 2006-09-19 Sanofi-Aventis Process for racemization
US6495691B1 (en) 2001-07-06 2002-12-17 Brantford Chemicals Inc. Process for the preparation of tetrahydrothieno[3,2-c]pyridine derivatives
WO2003035652A1 (en) * 2001-10-26 2003-05-01 Merck Generics [Uk] Limited A PROCESS FOR PREPARING ENANTIOMERICALLY PURE α-PHENYL-α-(6,7-DIHYDRO-4H-THIENO[3,2-C]PYRIDIN-5-YL)-ACETIC ACID DERIVATIVES
US6767913B2 (en) 2001-12-18 2004-07-27 Teva Pharmaceutical Industries Ltd. Crystal forms iii, iv, v, and novel amorphous form of clopidogrel hydrogensulfate, processes for their preparation, processes for the preparation of form i, compositions containing the new forms and methods of administering the new forms
US7074928B2 (en) 2002-01-11 2006-07-11 Teva Pharmaceutical Industries, Ltd. Polymorphs of clopidogrel hydrogensulfate
EP2168969A2 (en) 2002-08-02 2010-03-31 Teva Pharmaceutical Industries Ltd. Racemization and Enantiomer Separation of Clopidogrel
US7259261B2 (en) 2002-08-02 2007-08-21 TEVA Gyógyszergyár Zártkörűen Működő Részvénytársaság Racemization and enantiomer separation of clopidogrel
US6800759B2 (en) * 2002-08-02 2004-10-05 Teva Pharmaceutical Industries Ltd. Racemization and enantiomer separation of clopidogrel
US6737411B2 (en) * 2002-08-02 2004-05-18 Teva Pharmaceutical Industries Ltd. Racemization and enantiomer separation of clopidogrel
WO2004081016A1 (en) 2003-03-12 2004-09-23 Cadila Healthcare Limited Polymorphs and amorphous form of (s) - (+) -clopidogrel bisulfate
WO2004094374A2 (en) * 2003-04-23 2004-11-04 Rhodia Pharma Solutions Inc. (Formally Rhodia Chirex Inc.) Preparation of (s)-clopidogrel and related compounds
WO2004094374A3 (en) * 2003-04-23 2006-08-24 Rhodia Pharma Solutions Inc Fo Preparation of (s)-clopidogrel and related compounds
WO2004108665A3 (en) * 2003-04-24 2005-03-24 Sun Pharmaceutical Ind Ltd A process for preparation of clopidogrel
WO2004108665A2 (en) * 2003-04-24 2004-12-16 Sun Pharmaceutical Industries Limited A process for preparation of clopidogrel
EP2149578A1 (en) 2003-09-11 2010-02-03 Merck Generics (UK) Limited Novel crystalline polymorphs of clopidogrel
EP2103617A1 (en) 2003-11-03 2009-09-23 Cadila Healthcare Limited Processes for preparing different forms of (S)-(+)-clopidogrel bisulfate
WO2008118030A1 (en) * 2007-03-23 2008-10-02 Tomasz Kozluk Process for preparation of pure polymorphic form 1 of clopidogrel hydrogensulfate
EP1980563A1 (en) 2007-04-09 2008-10-15 BATTULA, Srinivasa Reddy Procedure for the preparation of methyl (+)-(S)-Alpha-(O-chlorophenyl)-6,7-dihydrothieno-[3,2-C]pyridine-5(4H) acetate
CN103483356A (zh) * 2013-09-30 2014-01-01 浙江美诺华药物化学有限公司 一种（s）-氯吡格雷的硫酸盐或盐酸盐的制备方法
CN103483356B (zh) * 2013-09-30 2016-01-13 浙江美诺华药物化学有限公司 一种（s）-氯吡格雷的硫酸盐或盐酸盐的制备方法

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BR9809111B1 (pt) 2009-05-05
JP2001525818A (ja) 2001-12-11
HUP9700884A3 (en) 2000-06-28
BR9809111A (pt) 2000-08-01
NO324039B1 (no) 2007-07-30
AU7444798A (en) 1998-12-08
NO995532L (no) 1999-12-13
HU225503B1 (en) 2007-01-29
DE69813792T2 (de) 2004-01-29
NO995532D0 (no) 1999-11-12
EP0981524B1 (en) 2003-04-23
CA2289545C (en) 2006-12-12
US6258961B1 (en) 2001-07-10
HU9700884D0 (en) 1997-07-28
EP0981524A1 (en) 2000-03-01
JP4282770B2 (ja) 2009-06-24
PT981524E (pt) 2003-08-29
DE69813792D1 (de) 2003-05-28
ES2195335T3 (es) 2003-12-01
ATE238294T1 (de) 2003-05-15
CA2289545A1 (en) 1998-11-19
HUP9700884A2 (hu) 1999-09-28

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